Pharmacokinetics and Tolerability of Oseltamivir Combined with Probenecid

Author:

Holodniy Mark123,Penzak Scott R.4,Straight Timothy M.5,Davey Richard T.6,Lee Kelvin K.37,Goetz Matthew Bidwell89,Raisch Dennis W.10,Cunningham Francesca11,Lin Emil T.12,Olivo Noemi3,Deyton Lawrence R.113

Affiliation:

1. Office of Public Health and Environmental Hazards, U.S. Department of Veterans Affairs, Washington, DC

2. Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, California

3. VA Palo Alto Health Care System, Palo Alto, California

4. Clinical Pharmacokinetics Research Laboratory, National Institutes of Health, Bethesda, Maryland

5. Department of Clinical Investigation, Brooke Army Medical Center, Ft. Sam Houston, Texas

6. CRS/LIR/NIAID, National Institutes of Health, Bethesda, Maryland

7. VA Cooperative Studies Program Coordinating Center, Palo Alto, California

8. Greater Los Angeles Health Care System, Los Angeles, California

9. Infectious Diseases Section, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California

10. VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico

11. Pharmacy Benefits Management Group, U.S. Department of Veterans Affairs, Hines, Illinois

12. Department of Biopharmaceutical Sciences, UCSF, San Francisco, California

13. George Washington University School of Medicine and Health Sciences, Washington, DC

Abstract

ABSTRACT Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) ( P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 ± 76 and 81 ± 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 ± 26 and 81 ± 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

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